The Pore-Forming Protein Gasdermin D Regulates Interleukin-1 Secretion from Living Macrophages

Immunity. 2018 Jan 16;48(1):35-44.e6. doi: 10.1016/j.immuni.2017.11.013. Epub 2017 Nov 28.


The interleukin-1 (IL-1) family cytokines are cytosolic proteins that exhibit inflammatory activity upon release into the extracellular space. These factors are released following various cell death processes, with pyroptosis being a common mechanism. Recently, it was recognized that phagocytes can achieve a state of hyperactivation, which is defined by their ability to secrete IL-1 while retaining viability, yet it is unclear how IL-1 can be secreted from living cells. Herein, we report that the pyroptosis regulator gasdermin D (GSDMD) was necessary for IL-1β secretion from living macrophages that have been exposed to inflammasome activators, such as bacteria and their products or host-derived oxidized lipids. Cell- and liposome-based assays demonstrated that GSDMD pores were required for IL-1β transport across an intact lipid bilayer. These findings identify a non-pyroptotic function for GSDMD, and raise the possibility that GSDMD pores represent conduits for the secretion of cytosolic cytokines under conditions of cell hyperactivation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Cell Membrane / metabolism
  • Enzyme-Linked Immunosorbent Assay
  • Flow Cytometry
  • Humans
  • Inflammasomes / metabolism
  • Interleukin-1beta / metabolism*
  • Intracellular Signaling Peptides and Proteins
  • Macrophages / metabolism*
  • Neoplasm Proteins / metabolism*
  • Phosphate-Binding Proteins
  • Protein Transport / physiology
  • Pyroptosis / immunology


  • GSDMD protein, human
  • Inflammasomes
  • Interleukin-1beta
  • Intracellular Signaling Peptides and Proteins
  • Neoplasm Proteins
  • Phosphate-Binding Proteins